Gastrointestinal disseminated histoplasmosis in HIV-infected patients: A descriptive and comparative study

Disseminated histoplasmosis is one the main AIDS-defining opportunistic infections in HIV-infected patients, notably in Latin America. The non-specific and proteiform clinical presentation leads to diagnostic delays that may lead to fatal outcomes. This retrospective multicentric study aimed to describe the frequency and manifestations of gastrointestinal histoplasmosis in French Guiana, and to compare patients with disseminated histoplasmosis with or without gastrointestinal involvement.Between January 1, 1981 and October 1, 2014 co-infections with HIV and histoplasmosis were enrolled. Inclusion criteria were: age >18 years, confirmed HIV infection; first proven episode of histoplasmosis.Among 349 cases of disseminated histoplasmosis, 245 (70%) had a gastrointestinal presentation. Half of patients with gastrointestinal signs had abdominal pain or diarrhea, mostly watery. Half of patients with abdominal pain had diarrhea (63/124) and half of those with diarrhea (63/123) had abdominal pain. A significant proportion of patients also had hepatomegaly and, to a lesser degree, splenomegaly. After adjusting for potential confounding, the presence of lymphadenopathies >2cm (AOR = 0.2, IC95 = 0.04–0.7, P = 0.01), Haitian origin (AOR = 0.04, IC95 = 0.004–0.4, P = 0.006) were associated with a lower prevalence of gastrointestinal signs and positive gastrointestinal presence of H. capsulatum. Persons with a gastrointestinal H. capsulatum were more likely to have a decreased prothrombin time, lower ferritin, lower liver enzymes, and lower concentrations of LDH than those without gastrointestinal signs and symptoms. They also had a shorter interval between symptoms onset and diagnosis. Patients with a positive gastrointestinal identification of H. capsulatum were less likely to die at 1 month than those without a gastrointestinal presentation (respectively, 4.6% vs 18.5%, P = 0.01).Subacute or chronic gastrointestinal presentations are very frequent during disseminated histoplasmosis, they seem less severe, and should lead to suspect the diagnosis in endemic areas. There were populational or geographic differences in the frequency of gastrointestinal manifestations that could not be explained.     

Regional differences in prostaglandin E2 and nitric oxide production in the knee meniscus in response to dynamic compression

Injury or loss of the knee meniscus is associated with altered joint stresses that lead to progressive joint degeneration. The goal of this study was to determine if dynamic mechanical compression influences the production of inflammatory mediators by meniscal cells. Dynamic compression increased prostaglandin E2 (PGE(2)) and nitric oxide (NO) production over a range of stress magnitudes (0.0125-0.5 MPa) in a manner that depended on stress magnitude and zone of tissue origin. Inner zone explants showed greater increases in PGE(2) and NO production as compared to outer zone explants. Meniscal tissue expressed NOS2 and NOS3 protein, but not NOS1. Mechanically induced NO production was blocked by NOS inhibitors, and the non-selective NOS inhibitor L-NMMA augmented PGE(2) production in the outer zone only. These findings suggest that the meniscus may serve as an intra-articular source of pro-inflammatory mediators, and that alterations in the magnitude or distribution of joint loading could significantly influence the production of these mediators in vivo.     

Phylogenetic Analysis of Bacterial Communities in Different Regions of the Gastrointestinal Tract of Agkistrodon piscivorus,the Cottonmouth Snake

Vertebrates are metagenomic organisms in that they are composed not only of their own genes but also those of their associated microbial cells. The majority of these associated microorganisms are found in the gastrointestinal tract (GIT) and presumably assist in processes such as energy and nutrient acquisition. Few studies have investigated the associated gut bacterial communities of non-mammalian vertebrates, and most rely on captive animals and/or fecal samples only. Here we investigate the gut bacterial community composition of a squamate reptile, the cottonmouth snake, Agkistrodon piscivorus through pyrosequencing of the bacterial 16S rRNA gene. We characterize the bacterial communities present in the small intestine, large intestine and cloaca. Many bacterial lineages present have been reported by other vertebrate gut community studies, but we also recovered unexpected bacteria that may be unique to squamate gut communities. Bacterial communities were not phylogenetically clustered according to GIT region, but there were statistically significant differences in community composition between regions. Additionally we demonstrate the utility of using cloacal swabs as a method for sampling snake gut bacterial communities.     

Energy intake and adiponectin gene expression

Hypoadiponectinemia and decreased adiponectin gene expression in white adipose tissue (WAT) have been well observed in obese subjects and animal models. However, the mechanism for obesity-associated hypoadiponectinemia is still largely unknown. To investigate the regulatory role of energy intake, dietary fat, and adiposity in adiponectin gene expression and blood adiponectin level, a series of feeding regimens was employed to manipulate energy intake and dietary fat in obese-prone C57BL/6, genetically obese ob/ob, obese-resistant A/J and peroxisome proliferator-activated receptor-α gene knockout (PPARα KO) mice. Adiponectin gene expression in WAT and circulating adiponectin levels were studied in these dietary intervention-treated mice. Our study showed that calorie restriction (CR) robustly increased adiponectin gene expression in epididymal fat and blood adiponectin levels in both low-fat (LF) and high-fat (HF) diet-fed C57BL/6 mice. Although HF pair-fed C57BL/6 mice received the same amount of calories as LF ad libitum-fed mice, HF diet clearly increased adiposity but showed no significant effects on adiponectin gene expression and blood adiponectin level. CR also significantly increased blood adiponectin levels in ob/ob and A/J mice. Neither CR nor HF feeding displayed any significant effect on blood adiponectin half-life in C57BL/6 mice. Interestingly, CR increased PPARα expression in epididymal fat of C57BL/6 mice. Low levels of blood adiponectin and adiponectin gene expression in WAT were observed in PPARα KO mice. PPARα agonist treatment increased adiponectin mRNA levels in 3T3-L1 adipocytes. Furthermore, CR failed to increase adiponectin gene expression and blood adiponectin levels in PPARα KO mice. Therefore, our study demonstrated that energy intake, not dietary fat, plays an important role in regulating adiponectin gene expression and blood adiponectin level. PPARα mediates CR-enhanced adiponectin gene expression in WAT.     

Upstream of N-Ras C-terminal cold shock domains mediate poly(A) specificity in a novel RNA recognition mode and bind poly(A) binding protein

RNA binding proteins (RBPs) often engage multiple RNA binding domains (RBDs) to increase target specificity and affinity. However, the complexity of target recognition of multiple RBDs remains largely unexplored. Here we use Upstream of N-Ras (Unr), a multidomain RBP, to demonstrate how multiple RBDs orchestrate target specificity. A crystal structure of the three C-terminal RNA binding cold-shock domains (CSD) of Unr bound to a poly(A) sequence exemplifies how recognition goes beyond the classical ππ-stacking in CSDs. Further structural studies reveal several interaction surfaces between the N-terminal and C-terminal part of Unr with the poly(A)-binding protein (pAbp). All interactions are validated by mutational analyses and the high-resolution structures presented here will guide further studies to understand how both proteins act together in cellular processes.     

Scaffolding as an organizing principle in trans-translation. The roles of small protein B and ribosomal protein S1

A eubacterial ribosome stalled on a defective mRNA can be released through a quality control mechanism referred to as trans-translation, which depends on the coordinating binding actions of transfer-messenger RNA, small protein B, and ribosome protein S1. By means of cryo-electron microscopy, we obtained a map of the complex composed of a stalled ribosome and small protein B, which appears near the decoding center. This result suggests that, when lacking a codon, the A-site on the small subunit is a target for small protein B. To investigate the role of S1 played in trans-translation, we obtained a cryo-electron microscopic map, including a stalled ribosome, transfer-messenger RNA, and small protein Bs but in the absence of S1. In this complex, several connections between the 30 S subunit and transfer-messenger RNA that appear in the +S1 complex are no longer found. We propose the unifying concept of scaffolding for the roles of small protein B and S1 in binding of transfer-messenger RNA to the ribosome during trans-translation, and we infer a pathway of sequential binding events in the initial phase of trans-translation.     

Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma

Charcot-Marie-Tooth disease (CMT) with autosomal recessive (AR) inheritance is a heterogeneous group of inherited motor and sensory neuropathies. In some families from Japan and Brazil, a demyelinating CMT, mainly characterized by the presence of myelin outfoldings on nerve biopsies, cosegregated as an autosomal recessive trait with early-onset glaucoma. We identified two such large consanguineous families from Tunisia and Morocco with ages at onset ranging from 2 to 15 years. We mapped this syndrome to chromosome 11p15, in a 4.6-cM region overlapping the locus for an isolated demyelinating ARCMT (CMT4B2). In these two families, we identified two different nonsense mutations in the myotubularin-related 13 gene, MTMR13. The MTMR protein family includes proteins with a phosphoinositide phosphatase activity, as well as proteins in which key catalytic residues are missing and that are thus called "pseudophosphatases." MTM1, the first identified member of this family, and MTMR2 are responsible for X-linked myotubular myopathy and Charcot-Marie-Tooth disease type 4B1, an isolated peripheral neuropathy with myelin outfoldings, respectively. Both encode active phosphatases. It is striking to note that mutations in MTMR13 also cause peripheral neuropathy with myelin outfoldings, although it belongs to a pseudophosphatase subgroup, since its closest homologue is MTMR5/Sbf1. This is the first human disease caused by mutation in a pseudophosphatase, emphasizing the important function of these putatively inactive enzymes. MTMR13 may be important for the development of both the peripheral nerves and the trabeculum meshwork, which permits the outflow of the aqueous humor. Both of these tissues have the same embryonic origin.